NHC-catalyzed enantioselective access to β-cyano carboxylic esters via in situ substrate alternation and release

A carbene-catalyzed asymmetric access to chiral β-cyano carboxylic esters is disclosed. The reaction proceeds between β,β-disubstituted enals and aromatic thiols involving enantioselective protonation of enal β-carbon. Two main factors contribute to the success of this reaction. One involves in situ ultrafast addition of the aromatic thiol substrates to the carbon-carbon double bond of the enal substrate. This reaction converts almost all enal substrate to a Thiol-click Intermediate, significantly reducing aromatic thiol substrates concentration and suppressing the homo-coupling reaction of enals. Another factor is an in situ release of enal substrate from the Thiol-click Intermediate for the desired reaction to proceed effectively. The optically enriched β-cyano carboxylic esters from our method can be readily transformed to medicines that include γ-aminobutyric acids derivatives such as Rolipram. In addition to synthetic utilities, our control of reaction outcomes via in situ substrate modulation and release can likely inspire future reaction development.

1. The substrate scope seems limited. Would β-alkyl-β-nitrile enals be applicable for this reaction? What about other nucleophiles such as amines instead of thiols? it's recommended to provide more attempts and details on the substrate scope. 2. There are some errors and typos need to be corrected. 1) Page 2, Table 2, footnote d should mark in entry 13. 2) Page 2, Line 132, "Various of substituents…"should be "Various substituents…".
3) Page 5, Line 199, 200 and 201, the character K of pKa should be italic. 4) Page 5, Line 220, "According to the research of key intermediates. The …" should be "According to the research of key intermediates, the …" 5) Page 6, Line 249, "bar, was add d 1a" should be "bar, was added 1a".
Reviewer #2: Remarks to the Author: Asymmetric synthesis of nitriles has attracted substantial attention among organic community. The traditional methods involve the metal-catalyzed coupling of alkenes with cyano sources and the catalytic hydrogenation of prochiral nitriles. Herein, Chi, Zheng and co-workers reported a new strategy for the enantioselective synthesis of chiral nitrile esters by NHC-catalyzed beta-protonation of prochiral nitrile enals. The reaction involved an interesting thiol-click intermediate which was determined to be the key success of this reaction. The substrate scope, synthetic application and reaction mechanism were well investigated and demonstrated. Basically, this work merits publication in Nat. Commun., but some issues need to be addressed.
1. As for naming the title compounds, is "beta-cyano carboxylic esters" more suitable than "betanitrile carboxylic esters"? 2. A recent asymmetric synthesis of nitriles via cooperative organocatalysis and PC catalysis needs to be included in introduction section (Nature Catalysis, 2023, doi.org/10.1038/s41929-023-00939-y). More reviews of NHC-organocatalysis need to be included. 3. How to explain that the er values of 3f-h decreased significantly? 4. Examples of alfa-substituted enals need to be tested to further expand the utility of this protocol. 5. A control experiment of the conversion of Intermediate I to product 3a under NHC catalysis needs be included. 6. Please adjust the figures in Page S84.
Enclosed is our revised manuscript " NHC-Catalyzed Enantioselective Access to -Nitrile

Carboxylic Esters via In Situ Substrate Alternation and Release "
We are pleased by the supporting comments from all the reviewers. A point-by-point response to the editorial requests and referee comments is included in this letter.

Response to Reviewer #1
Reviewer #1 has recommended publication after addressing the following concerns and questions. 1). The substrate scope seems limited. Would β-alkyl-β-nitrile enals be applicable for this reaction? What about other nucleophiles such as amines instead of thiols? it's recommended to provide more attempts and details on the substrate scope.
Our Response: 1-1. The referee is right it will be valuable for this chemistry to work with β-alkyl substrates.
Unfortunately, at this point we face technical difficulties to prepare such β-alkyl enals. We have tried a few common synthetic routes to prepare such substrate, but without success. A few of our attempted routes are shown below. We'll look into this matter again when there is a need in the future. Table 1 (Page 2, line 67), we attempted other nucleophiles to replace thiols such as amines to react with 1a. The results were listed in Table R1. Table R1. Initial studies of nucleophiles a .
3. Page 5, Line 199, 200 and 201, the character K of pKa should be italic.
4. Page 5, Line 220, "According to the research of key intermediates. The …" should be "According to the research of key intermediates, the …" 5. Page 6, Line 249, "bar, was add d 1a" should be "bar, was added 1a".
Our Response: We have revised the above comments in the revised manuscript.

Response to Reviewer #2
Reviewer #2 has recommended publication, but some issues need to be addressed.
Our Response: We have revised the comment in the revised manuscript.
2). A recent asymmetric synthesis of nitriles via cooperative organocatalysis and PC catalysis needs to be included in introduction section (Nature Catalysis, 2023, doi.org/10.1038/s41929-023-00939-y). More reviews of NHC-organocatalysis need to be included.
Our Response: Revised.
3). How to explain that the er values of 3f-h decreased significantly?
Our Response: Products containing electron withdrawing group such as chrolo-and bromo-atoms (3f-3h), the β-CH is more acidic which will lead to racemization of the products. Therefore, several controlled experiments were carried out, er value of product 3f in different reaction time were monitored. It was found that the er value decreased gradually with the extension of reaction time.